Food standards agency atypical scrapie contingency plan Issue 1. In June 2006 the Food Standards Agency (FSA) Board considered current precautionary risk management measures for small ruminants. The Board agreed that current precautionary measures were sufficient. However, they wished to develop a contingency plan in case SEAC’s understanding of the risk of atypical scrapie for human health changed. To inform this contingency plan the FSA requested SEAC advice on potential outcomes of research on atypical scrapie, or surveillance results, that may lead to a change in SEAC’s estimate of the risk to human health.

Background2. In February 2006 the SEAC sheep subgroup published a position statement on atypical scrapie1 which concluded that atypical scrapie should be considered a distinct transmissible spongiform encephalopathy (TSE) of small ruminants and not simply a variant of classical scrapie. While there was no evidence that atypical scrapie could infect humans, a theoretical risk could not be excluded. SEAC concluded, however, that there were insufficient data available to adequately assess the potential risks to human health. The subgroup recommended that an adequate assessment of the potential risk to human health of atypical scrapie might come from studies on the prevalence, transmission in animal models, tissue distribution and human health surveillance.

3. SEAC considered the potential significance of the outcomes of these areas of research for the human health risk from atypical scrapie, based on scenarios put forward by the FSA2.

Prevalence 4. The SEAC sheep subgroup statement concludes that there could be around 82,000 sheep in the UK infected with atypical scrapie. Future surveillance and epidemiological studies along with the analysis of sheep brain tissue samples dating back to 1964 may confirm the historical presence of the disease, changes in prevalence over time, and whether or not atypical scrapie may occur in countries previously thought to be free from classical and atypical scrapie. SEAC considered that the identification of historical cases, new cases in scrapie-free countries, and changes in prevalence of atypical scrapie would be significant from a public health perspective. If such data indicate that atypical scrapie has been present for many years, and is not increasing in prevalence then, by analogy with classical scrapie the human health risk would be considered low. However, if atypical scrapie were found to be spreading rapidly, this would imply it is a new disease and any human health risk would be more uncertain. It is therefore important to continue to assess the historic prevalence of atypical scrapie, and for archived sheep samples be analysed for the presence of the disease.

5. A human health risk would only be confirmed by concomitant changes in the prevalence of new types of Creutzfeldt-Jakob Disease (CJD). Because of the long incubation periods of prion diseases, such data may not become apparent for many years, although atypical scrapie has been identified in a UK sheep from 1989, implying that humans may have been exposed to atypical scrapie via the dietary route for a number of years. In the absence of data suggesting a link to a new type of CJD SEAC would be unlikely to change its current assessment of the human health risk.

Transmission studies 6. Results from transmission studies using non-human primates, particularly via the oral route, would strongly inform the understanding of human health risk. The immune and lymphoreticular systems of non-human primates are closely related to those of humans and the peripheral pathogenesis of TSEs in non-human primates mimics that in humans. However, non-human primates only provide data relating to one genotype, MM, which comprises about 37% of the UK population3. Assessment of the level of risk would require comparison with transmissions of other TSEs in the same models, in particular BSE, some of which are already available.

7. Humanised mice can provide data on all three human prion protein genotypes. It is important to be aware of the possibility that such mice may not show any clinical sign of infection after primary transmission of atypical scrapie, yet a secondary transmission from these animals to others may result in clinical disease due to loss of the interspecies transmission barrier. Although humanised mice are a good model for human disease, it will be critical to compare the behaviour of atypical scrapie with other TSEs, especially classical scrapie and BSE, in several mouse models after secondary transmission in order to obtain the most reliable risk assessments.

8. The barrier to transmission of atypical scrapie between animal and human can be tested in vitro by cell free conversion assays. However, care is needed in interpreting the significance of such experiments as ex vivo data do not always correlate well with in vivo studies. Nevertheless, they could provide data on whether conversion of the normal prion protein in humans to the abnormal form by the atypical scrapie prion is or is not possible.

Tissue Distribution 9. Little is known about the tissue distribution of abnormal prion protein (PrPsc) and infectivity in sheep with atypical scrapie. If atypical scrapie is found to be a health risk to humans, data from studies to assess the tissue distribution of PrPsc and infectivity are essential to allow an assessment of the risk under specific control measures.

Human Health 10. Establishing a definitive link between an animal and a human TSE is extremely difficult. Animal model data will only be indicative, and not definitive, although if carried out appropriately could be strongly indicative of a human health risk. The emergence of a new type of CJD which shows the same transmission characteristics as atypical scrapie in non-human primates and humanised mice would provide a strong indication that transmission had occurred through the consumption of infected material. Thus, ongoing human surveillance is critical.

11. It is difficult to conclude that atypical scrapie is not a human health risk from negative experimental or surveillance results. However, negative results from current and retrospective surveillance and transmission studies, over a significant period of time to allow for possibly long incubation periods, would imply a negligible human health risk.

Conclusion 12. It is not possible to assess the human health risk from atypical scrapie, or changes in risk, in the absence of hard scientific data. No single data set is likely to be definitive and it would be essential to consider all the information available, rather than data from single studies in isolation. Studies comparing the properties of atypical scrapie and other TSE agents using the same animal model, especially humanised mice or non-human primates, would be most informative in the short term. Surveillance data to assess any association between forms of CJD and atypical scrapie prevalence would be most persuasive but are unlikely to become available in the short term. SEAC would have to review experimental methods and results, should they emerge, before any conclusion of a change to the risk to human health from atypical scrapie could be made.

Edited by Stanley B. Prusiner, University of California, San Francisco, CA,and approved September 12, 2005 (received for review March 21, 2005)

Scrapie in small ruminants belongs to transmissible spongiformencephalopathies (TSEs), or prion diseases, a family of fatalneurodegenerative disorders that affect humans and animals and can transmitwithin and between species by ingestion or inoculation. Conversion of thehost-encoded prion protein (PrP), normal cellular PrP (PrPc), into amisfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmissionand pathogenesis. The intensified surveillance of scrapie in the EuropeanUnion, together with the improvement of PrPSc detection techniques, has ledto the discovery of a growing number of so-called atypical scrapie cases.These include clinical Nor98 cases first identified in Norwegian sheep onthe basis of unusual pathological and PrPSc molecular features and "cases"that produced discordant responses in the rapid tests currently applied tothe large-scale random screening of slaughtered or fallen animals.Worryingly, a substantial proportion of such cases involved sheep with PrPgenotypes known until now to confer natural resistance to conventionalscrapie. Here we report that both Nor98 and discordant cases, includingthree sheep homozygous for the resistant PrPARR allele (A136R154R171),efficiently transmitted the disease to transgenic mice expressing ovine PrP,and that they shared unique biological and biochemical features uponpropagation in mice. These observations support the view that a trulyinfectious TSE agent, unrecognized until recently, infects sheep and goatflocks and may have important implications in terms of scrapie control andpublic health.

Edited by D. Carleton Gajdusek, Centre National de la RechercheScientifique, Gif-sur-Yvette, France, and approved December 7, 2000(received for review October 16, 2000)

Abstract

There is substantial scientific evidence to support the notion thatbovine spongiform encephalopathy (BSE) has contaminated human beings,causing variant Creutzfeldt-Jakob disease (vCJD). This disease hasraised concerns about the possibility of an iatrogenic secondarytransmission to humans, because the biological properties of theprimate-adapted BSE agent are unknown. We show that (i) BSE can betransmitted from primate to primate by intravenous route in 25 months,and (ii) an iatrogenic transmission of vCJD to humans could be readilyrecognized pathologically, whether it occurs by the central orperipheral route. Strain typing in mice demonstrates that the BSE agentadapts to macaques in the same way as it does to humans and confirmsthat the BSE agent is responsible for vCJD not only in the UnitedKingdom but also in France. The agent responsible for French iatrogenicgrowth hormone-linked CJD taken as a control is very different from vCJDbut is similar to that found in one case of sporadic CJD and one sheepscrapie isolate. These data will be key in identifying the origin ofhuman cases of prion disease, including accidental vCJD transmission,and could provide bases for vCJD risk assessment.

Introduction

The recognition of a variant of the human transmissible spongiformencephalopathy (TSE) Creutzfeldt-Jakob Disease (vCJD) in the U.K. in1996 raised the major concern that it would correspond to humaninfection with the agent responsible for bovine spongiformencephalopathy (BSE; ref. 1). Transmission of BSE to macaques providedthe first experimental evidence as it produced a disease close to vCJDin humans (2). Strain typing in inbred mice (consisting of measuring theincubation period and establishing lesion profiles corresponding to thestrain-specific distribution of brain vacuolation) allows reliableidentification of TSE strains (3). This method, together withbiochemical methods, has revealed a single phenotype for the agents ofBSE and the British cases of vCJD (4-6). Mice expressing only the bovineprion protein (PrP) were highly susceptible to vCJD and BSE, whichinduced the same disease (7). Thus, it is now well established that BSEhas caused vCJD, probably by alimentary contamination. In this respect,the finding of abnormal PrP labeling in the gastrointestinal tract andlymphatic tissues of orally BSE-contaminated lemurs shows that the BSEagent can infect primates by the oral route (8). About 1 millioncontaminated cattle may have entered the human food chain, and thefuture number of vCJD cases could range from 63 to 136,000 depending onthe incubation period of BSE in humans (9). Unlike sporadic CJD (sCJD)and iatrogenic CJD (iCJD) linked to the administration of contaminatedgrowth hormone extracted from human hypophyses, in vCJD, the infectiousagent seems to be widely distributed in lymphoid organs, as pathologicalPrP (PrPres) can be detected in tonsils, lymph nodes, spleen, andappendix even in the preclinical phase of the disease (10, 11). Thisraises a public health issue with regard to the risk of iatrogenictransmission of vCJD through surgical instruments, grafts, bloodtransfusion, or parenteral administration of biological products ofhuman origin. However, this risk is difficult to assess, because itlargely depends on factors such as the virulence of the BSE agentadapted to primates and the efficiency of secondary transmission tohumans by a peripheral route such as the i.v. one. A further issue iswhether vCJD accidentally acquired from humans would be recognized. Thelatter poses the question of a phenotypic variation of the BSE agentafter successive transmissions in humans: does it retain its straincharacteristics, and does it induce a pathology similar to that observedin the previous host? A 9-year history of transmission of BSE toprimates and mice enables us today to clarify a number of theseimportant points.

Although BSE has mainly affected the U.K., two definite cases and oneprobable case of vCJD have now been reported in France in people whohave never resided in the U.K. (12, 13). We strain-typed the first ofthese cases to establish its origin. Strain typing in C57BL/6 mice ofBSE, French, and British vCJD was compared with that of BSE passaged innonhuman primates, thus allowing us to study the effect of serialpassages in primates. Comparisons were also made with French cases ofsCJD and iCJD and two strains of scrapie (one of French and one of U.S.origin). Our findings provide experimental demonstration that the sameagent, namely that responsible for the cattle disease BSE, has causedvCJD both in France and in the U.K., in line with biochemical data andwith the fact that, until 1996, about 10% of the beef consumed in Francewas imported from the U.K. We found that the BSE agent in nonhumanprimates is similar to that causing vCJD in humans and tends to evolverapidly toward a primate-adapted variant. Furthermore, we showed thatthe strain responsible for iCJD is closely related to that of onepatient with sCJD, and, more unexpectedly, that these agents weresimilar to the French scrapie strain studied (but different from theU.S. scrapie strain). This finding requires a cautious interpretationfor several reasons, not least because of the inevitably limited numberof TSE strains that can be studied by such a cumbersome method as straintyping. Nonetheless, it also prompts reconsideration of the possibilitythat, in some instances, sheep and human TSEs can share a common origin.

Chronic wasting disease (CWD) is a transmissiblespongiform encephalopathy (TSE) of deer and elk,and little is known about its transmissibility to otherspecies. An important factor controllinginterspecies TSE susceptibility is prion protein (PrP)homology between the source and recipientspecies/genotypes. Furthermore, the efficiency with whichthe protease-resistant PrP (PrP-res) of onespecies induces the in vitro conversion of the normal PrP(PrP-sen) of another species to theprotease-resistant state correlates with the cross-speciestransmissibility of TSE agents. Here weshow that the CWD-associated PrP-res (PrPCWD) of cervidsreadily induces the conversion of recombinant cervid PrP-senmolecules to the protease-resistant state in accordancewith the known transmissibility of CWD between cervids. In contrast,PrPCWD-induced conversions of human and bovine PrP-sen weremuch less efficient, and conversion of ovine PrP-sen wasintermediate. These results demonstrate a barrier at themolecular level that should limit the susceptibility of these non-cervidspecies to CWD.

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Clearly, it is premature to draw firm conclusions about CWDpassing naturally into humans, cattle and sheep, but the presentresults suggest that CWD transmissions to humans would be aslimited by PrP incompatibility as transmissions of BSE or sheepscrapie to humans. Although there is no evidence that sheepscrapie has affected humans, it is likely that BSE has caused variantCJD in 74 people (definite and probable variant CJD cases todate according to the UK CJD Surveillance Unit). Given thepresumably large number of people exposed to BSE infectivity,the susceptibility of humans may still be very low compared withcattle, which would be consistent with the relatively inefficientconversion of human PrP-sen by PrPBSE. Nonetheless, sincehumans have apparently been infected by BSE, it would seem prudentto take reasonable measures to limit exposure of humans(as well as sheep and cattle) to CWD infectivity as has beenrecommended for other animal TSEs.

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http://www.emboj.org/current.shtml

Scrapie to Humans?

Neuroepidemiology. 1985;4(4):240-9. Related Articles, Links

Sheep consumption: a possible source of spongiform encephalopathy in humans.

Davanipour Z, Alter M, Sobel E, Callahan M.

A fatal spongiform encephalopathy of sheep and goats (scrapie) shares manycharacteristics with Creutzfeldt-Jakob disease (CJD), a similar dementingillness of humans. To investigate the possibility that CJD is acquired byingestion of contaminated sheep products, we collected information onproduction, slaughtering practices, and marketing of sheep in Pennsylvania.The study revealed that sheep were usually marketed before central nervoussystem signs of scrapie are expected to appear; breeds known to besusceptible to the disease were the most common breeds raised in the area;sheep were imported from other states including those with a high frequencyof scrapie; use of veterinary services on the sheep farms investigated and,hence, opportunities to detect the disease were limited; sheep producers inthe area knew little about scrapie despite the fact that the disease hasbeen reported in the area, and animal organs including sheep organs weresometimes included in processed food. Therefore, it was concluded that inPennsylvania there are some 'weak links' through which scrapie-infectedanimals could contaminate human food, and that consumption of these foodscould perhaps account for spongiform encephalopathy in humans. The weaklinks observed are probably not unique to Pennsylvania.

Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheepand goats were transmitted to squirrel monkeys (Saimiri sciureus) that wereexposed to the infectious agents only by their nonforced consumption ofknown infectious tissues. The asymptomatic incubation period in the onemonkey exposed to the virus of kuru was 36 months; that in the two monkeysexposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months,respectively; and that in the two monkeys exposed to the virus of scrapiewas 25 and 32 months, respectively. Careful physical examination of thebuccal cavities of all of the monkeys failed to reveal signs or orallesions. One additional monkey similarly exposed to kuru has remainedasymptomatic during the 39 months that it has been under observation.

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The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease. ...end (from full text study pdf...TSS)

This is provided by the statistically significant increase in the incidenceof sheep scrape from 1985, as determined from analyses of the submissionsmade to VI Centres, and from individual case and flock incident studies.........

http://www.bseinquiry.gov.uk/files/yb/1994/02/07002001.pdf

12/10/76AGRICULTURAL RESEARCH COUNCILREPORT OF THE ADVISORY COMMITTE ON SCRAPIEOffice NoteCHAIRMAN: PROFESSOR PETER WILDY

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A The Present Position with respect to ScrapieA] The Problem

Scrapie is a natural disease of sheep and goats. It is a slowand inexorably progressive degenerative disorder of the nervous systemand it ia fatal. It is enzootic in the United Kingdom but not in allcountries.

The field problem has been reviewed by a MAFF working group(ARC 35/77). It is difficult to assess the incidence in Britain fora variety of reasons but the disease causes serious financial loss;it is estimated that it cost Swaledale breeders alone $l.7 M duringthe five years 1971-1975. A further inestimable loss arises from theclosure of certain export markets, in particular those of the UnitedStates, to British sheep.

It is clear that scrapie in sheep is important commercially andfor that reason alone effective measures to control it should bedevised as quickly as possible.

Recently the question has again been brought up as to whetherscrapie is transmissible to man. This has followed reports that thedisease has been transmitted to primates. One particularly luridspeculation (Gajdusek 1977) conjectures that the agents of scrapie,kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy ofmink are varieties of a single "virus". The U.S. Department ofAgriculture concluded that it could "no longer justify or permitscrapie-blood line and scrapie-exposed sheep and goats to be processedfor human or animal food at slaughter or rendering plants" (ARC 84/77)"The problem is emphasised by the finding that some strains of scrapieproduce lesions identical to the once which characterise the humandementias"

Whether true or not. the hypothesis that these agents might betransmissible to man raises two considerations. First, the safetyof laboratory personnel requires prompt attention. Second, actionsuch as the "scorched meat" policy of USDA makes the solution of theacrapie problem urgent if the sheep industry is not to suffergrievously.